Large granular lymphocyte leukemia (LGL) is a rare form of lymphoproliferative disorder often associated with autoimmune disease (Loughran T. P., Clonal diseases of large granular lymphocytes. Blood 82, 1–14, 1993).
The cause of LGL is still not fully understood. An increased count of large granular lymphocytes is characteristic of LGL leukemia. Patients with clonal CD3+LGL, as determined by cytogenetic or T-cell receptor (TCR) gene rearrangement studies, are classified as T-LGL. Some of these patients may resemble those with Felty's syndrome with clinical features of rheumatoid arthritis, neutropenia and splenomegaly (Ahern M. J., et al., P. Phenotypic and genotypic analysis of mononuclear cells from patients with Felty's syndrome. Ann. Rheum. 49, 103–108, 1990.) Morbidity and mortality in patients with LGL leukemia typically results from infections acquired during severe neutropenia.
The etiology of LGL leukemia is also not yet known. There is strong evidence that suggests that leukemic large granular lymphocytes are antigen activated cytotoxic T lymphocytes (CTL), but the nature of the antigen and of the initial stimulus leading to antigen driven expansion are not known.
LGL leukemic cells express FAS and FAS ligand, but they are not actively undergoing apoptosis (Perzova, R and Loughran, T. P, Jr. Constitutive expression of Fas ligand in large granular lymphocyte leukemia. British Jnl. Haematology, 1997). How they acquire resistance to apoptosis is not known.
Within the field of the diagnosis and treatment of LGL and other autoimmune diseases, there is a need for better tools for diagnosis and early detection of disease, specific therapeutic targets and treatments for the disease, and more specific reagents and tools with which to identify the pathogenic pathways of these diseases. The present invention provides a novel gene and splice variants that are linked to these diseases, and which address the aforementioned needs and more, as will become clear to one of skill in the art upon reading the following disclosure.